Research reveals the surprising clumping of misfolded proteins

Research reveals the surprising clumping of misfolded proteins

Research at the Stowers Institute for Medical Research revealed the aggregates of misfolded cellular proteins linked to age-related disorders including Parkinson’s disease. The research was issued in the journal Cell. The researchers used 3-D time-lapse movies to track the fate of misfolded proteins in yeast cells.

The findings of the study challenged the concept of the aggregation process as a passive effect of accruing misfolded proteins.

The research determines that 90 percent of the aggregates form on the surface of the endoplasmic reticulum (ER). ER is the location of protein synthesis in the cell. It was believed that misfolded proteins clump together in the cytosol spontaneously. The cytosol is the fluid component of a cell’s interior.

Budding yeast or Saccharomyces cerevisiae is a frequently used laboratory model in aging research. Stowers’ scientists opted for it. They experimentally used heat and other forms of stress to clump together the misfolded proteins.

The researchers also found that the misfolded proteins aggregate on the ER surface due to the active synthesis of proteins by ribosomes. The ribosomes generate a linear polypeptide chain i.e. the initial form of a protein. This newly synthesized polypeptide folds into a characteristic three-dimensional structure and results in a functionally shaped protein. Proteins that fail to do so appropriately cannot perform their biological functions. Moreover, they are potentially toxic to cells.

The research concludes that the aggregation of misfolded or unfolded proteins are helpful in protecting the cell and preventing their transfer to daughter cells during cell division.

Protein aggregation requires active translation

Furthermore, in order to determine that protein aggregation requires active translation for regulation, the scientists at Stowers reveal that the mitochondria play a key role in the mobility of this protein aggregates. Mitochondria are powerhouses of the cells. The majority of the proteins are found to aggregate in regions where ER and mitochondria come together. This might be surprising but fits well with the view of regulated aggregation.

The previous studies published in the journal Cell are based upon a similar concept. They reveal that most aggregates of unfolded proteins retain in the mother yeast cell during the asymmetric cell division. It might characterize not only this organism but stem cells also. Budding yeast reproduces by small outgrowths or buds. These buds outgrow of the mother yeast cell and become a daughter cell.

This respective research identifies the quality control mechanisms. These mechanisms work to limit the spreading of the misfolded protein aggregates to the bud or the daughter cell. During the mitotic division of budding yeast, aggregates of abnormal protein are tied to well-anchored mitochondria in the mother cell. Resultantly, the mitochondria acquired by the bud are largely free of the abnormal aggregates.

According to the research team, the majority of aggregates present in the mother, the cell didn’t follow the mitochondria that entered the bud. However, they either underwent dissolution or remained associated with the mitochondria in the mother cell. They only exhibited restricted local mobility. The bud-inherited mitochondria were largely devoid of aggregates.

Additional findings

The disruption of the aggregate-mitochondria association increased the mobility and leakage of mother-accumulated aggregates into the bud. The researchers also verified that the aggregate-mitochondria association gradually declines in the mother budding yeast cells. This is because of the advanced replicative age that contributes to their weakened ability to restore through asymmetric cell division.

The researchers could visualize the process because the protein aggregates were labeled differently with fluorescently tagged proteins, binding to the aggregates. The research was assisted with the Electron Microscopy and Imaging core centers at the Stowers Institute.

The author is a Medical Microbiologist and healthcare writer. She is a post-graduate of Medical Microbiology and Immunology. She covers all content on health and wellness including weight loss, nutrition, and general health. Twitter @Areeba94789300

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